Advertisement

Tumor-Infiltrating Lymphocytes (TIL), Tertiary Lymphoid Structures (TLS), and Expression of PD-1, TIM-3, LAG-3 on TIL in Invasive and In Situ Ductal Breast Carcinomas and Their Relationship with Prognostic Factors

Published:August 19, 2022DOI:https://doi.org/10.1016/j.clbc.2022.08.005

      Abstract

      Introduction

      Immunotherapy has been determined as an important choice in breast carcinomas, especially in tumors with markedly inflammatory response. About this promising subject, tumor-infiltrating lymphocytes (TIL) and the expression of immune control point receptors on TIL have gained importance.

      Materials and Methods

      In this study, stromal TIL and tertiary lymphoid structures (TLS) were determined in tumor tissues of 312 invasive and 68 in situ breast cancer patients. Expression rates of PD-1, LAG-3, and TIM-3 on intratumoral and stromal TIL were immunohistochemically evaluated.

      Results

      In invasive breast carcinomas, stromal TIL was found to be significantly associated with lymph node metastasis, HR and HER2 expression, and basal-like phenotype, as the presence of TLS with neoadjuvant therapy, recurrence, death, and expression of HR and HER2. PD-1, LAG-3, and TIM-3 expressions were found to be associated with HR and HER2 status, stromal TIL rates, and TLS. In multivariate analysis, high stromal TIL and PD-1 expression in intratumoral TIL were found to be independent prognostic factors in terms of overall survival and disease-free survival.

      Conclusion

      Evaluation of TIL and immune control point receptor expressions in breast cancer is particularly important in terms of planning the therapeutic approaches based on immunotherapy protocols.

      Keywords

      Abbreviations:

      TIL (Tumor-Infiltrating Lymphocytes), TLS (Tertiary Lymphoid Structures)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Breast Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bray F
        • Ferlay J
        • Soerjomataram I
        • Siegel RL
        • Torre LA
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424https://doi.org/10.3322/caac.21492
        • Prat A
        • Pineda E
        • Adamo B
        • et al.
        Clinical implications of the intrinsic molecular subtypes of breast cancer.
        Breast. 2015; 24 (Edinburgh, Scotland): S26-S35https://doi.org/10.1016/j.breast.2015.07.008
        • Brignone C
        • Gutierrez M
        • Mefti F
        • et al.
        First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity.
        J Transl Med. 2010; 8: 71https://doi.org/10.1186/1479-5876-8-71
      1. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). AACR; 2015. doi:10.1158/1538-7445.AM2015-2859

        • Migali C
        • Milano M
        • Trapani D
        • et al.
        Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond.
        rapeutic advances med oncol. 2016; 8: 360-374https://doi.org/10.1177/1758834016658423
        • Abbas AK
        • Lichtman AH
        • Pillai S.
        Cellular and Molecular Immunology E-Book.
        Elsevier Health Sciences, California2014
        • Anderson AC
        • Joller N
        • Kuchroo VK.
        Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation.
        Immunity. 2016; 44: 989-1004https://doi.org/10.1016/j.immuni.2016.05.001
        • Dieci MV
        • Radosevic-Robin N
        • Fineberg S
        • et al.
        Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the international immuno-oncology biomarker working group on breast cancer.
        Semin Cancer Biol. 2018; 52: 16-25https://doi.org/10.1016/j.semcancer.2017.10.003
        • Stanton SE
        • Disis ML.
        Clinical significance of tumor-infiltrating lymphocytes in breast cancer.
        J Immunother Cancer. 2016; 4: 59https://doi.org/10.1186/s40425-016-0165-6
        • Hiraoka N
        • Ino Y
        Yamazaki-Itoh R. tertiary lymphoid organs in cancer tissues.
        Front Immunol. 2016; 7: 244https://doi.org/10.3389/fimmu.2016.00244
        • Dieu-Nosjean MC
        • Antoine M
        • Danel C
        • et al.
        Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures.
        J Clin Oncol. 2008; 26: 4410-4417https://doi.org/10.1200/JCO.2007.15.0284
        • Trajkovski G
        • Ognjenovic L
        • Karadzov Z
        • et al.
        Tertiary lymphoid structures in colorectal cancers and their prognostic value.
        Open access Macedonian J med sci. 2018; 6: 1824-1828https://doi.org/10.3889/oamjms.2018.341
        • Cabrita R
        • Lauss M
        • Sanna A
        • et al.
        Tertiary lymphoid structures improve immunotherapy and survival in melanoma.
        Nature. 2020; 577: 561-565https://doi.org/10.1038/s41586-019-1914-8
        • Liu X
        • Tsang JYS
        • Hlaing T
        • et al.
        Distinct tertiary lymphoid structure associations and their prognostic relevance in HER2 positive and negative breast cancers.
        Oncologist. 2017; 22: 1316-1324https://doi.org/10.1634/theoncologist.2017-0029
        • Sofopoulos M
        • Fortis SP
        • Vaxevanis CK
        • et al.
        The prognostic significance of peritumoral tertiary lymphoid structures in breast cancer.
        Cancer Immunol Immunother. 2019; 68: 1733-1745https://doi.org/10.1007/s00262-019-02407-8
        • Salgado R
        • Denkert C
        • Demaria S
        • et al.
        The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.
        Ann Oncol. 2015; 26: 259-271https://doi.org/10.1093/annonc/mdu450
        • Denkert C
        • von Minckwitz G
        • Darb-Esfahani S
        • et al.
        Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy.
        Lancet Oncol. 2018; 19: 40-50https://doi.org/10.1016/S1470-2045(17)30904-X
        • Loi S
        • Michiels S
        • Salgado R
        • et al.
        Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.
        Ann Oncol. 2014; 25: 1544-1550https://doi.org/10.1093/annonc/mdu112
        • Kim S
        • Park S
        • Cho MS
        • Lim W
        • Moon BI
        • Sung SH.
        Strong correlation of indoleamine 2,3-dioxygenase 1 expression with basal-like phenotype and increased lymphocytic infiltration in triple-negative breast cancer.
        J Cancer. 2017; 8: 124-130https://doi.org/10.7150/jca.17437
        • Heng YJ
        • Lester SC
        • Tse GM
        • et al.
        The molecular basis of breast cancer pathological phenotypes.
        J Pathol. 2017; 241: 375-391https://doi.org/10.1002/path.4847
        • Thomas A
        • Routh ED
        • Pullikuth A
        • et al.
        Tumor mutational burden is a determinant of immune-mediated survival in breast cancer.
        Oncoimmunology. 2018; 7 (e1490854)https://doi.org/10.1080/2162402X.2018.1490854
        • Liubomirski Y
        • Lerrer S
        • Meshel T
        • et al.
        Tumor-stroma-inflammation networks promote pro-metastatic chemokines and aggressiveness characteristics in triple-negative breast cancer.
        Front Immunol. 2019; 10: 757https://doi.org/10.3389/fimmu.2019.00757
        • Jamshidi N
        • Yamamoto S
        • Gornbein J
        • Kuo MD.
        Receptor-based surrogate subtypes and discrepancies with breast cancer intrinsic subtypes: implications for image biomarker development.
        Radiology. 2018; 289: 210-217https://doi.org/10.1148/radiol.2018171118
        • Loi S
        • Sirtaine N
        • Piette F
        • et al.
        Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.
        J Clin Oncol. 2013; 31: 860-867https://doi.org/10.1200/JCO.2011.41.0902
        • Salgado R
        • Denkert C
        • Campbell C
        • et al.
        Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the neoaltto trial.
        JAMA Oncol. 2015; 1: 448-454https://doi.org/10.1001/jamaoncol.2015.0830
        • Liu JY
        • Yang GF
        • Chen FF
        • Peng CW.
        Evaluating the prognostic significance of tumor-infiltrating lymphocytes in solid tumor: practice of a standardized method from the international immuno-oncology biomarkers working group.
        Cancer manage res. 2019; 11: 6815-6827https://doi.org/10.2147/CMAR.S201538
        • Jang N
        • Kwon HJ
        • Park MH
        • Kang SH
        • Bae YK.
        Prognostic value of tumor-infiltrating lymphocyte density assessed using a standardized method based on molecular subtypes and adjuvant chemotherapy in invasive breast cancer.
        Ann Surg Oncol. 2018; 25: 937-946https://doi.org/10.1245/s10434-017-6332-2
        • Figenschau SL
        • Fismen S
        • Fenton KA
        • Fenton C
        • Mortensen ES.
        Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients.
        BMC Cancer. 2015; 15: 101https://doi.org/10.1186/s12885-015-1116-1
        • Lee HJ
        • Kim JY
        • Park IA
        • et al.
        Prognostic significance of tumor-infiltrating lymphocytes and the tertiary lymphoid structures in her2-positive breast cancer treated with adjuvant trastuzumab.
        Am J Clin Pathol. 2015; 144: 278-288https://doi.org/10.1309/AJCPIXUYDVZ0RZ3G
        • Lee HJ
        • Park IA
        • Song IH
        • et al.
        Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer.
        J Clin Pathol. 2016; 69: 422-430https://doi.org/10.1136/jclinpath-2015-203089
        • Tsang JY
        • Au WL
        • Lo KY
        • et al.
        PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients.
        Breast Cancer Res Treat. 2017; 162: 19-30https://doi.org/10.1007/s10549-016-4095-2
        • Kitano A
        • Ono M
        • Yoshida M
        • et al.
        Tumour-infiltrating lymphocytes are correlated with higher expression levels of PD-1 and PD-L1 in early breast cancer.
        ESMO open. 2017; 2e000150https://doi.org/10.1136/esmoopen-2016-000150
        • Noske A
        • Möbus V
        • Weber K
        Relevance of tumour-infiltrating lymphocytes, PD-1 and PD-L1 in patients with high-risk, nodal-metastasised breast cancer of the German Adjuvant Intergroup Node-positive study.
        Eur J Cancer. 2019; 114 (Oxford, England: 1990): 76-88https://doi.org/10.1016/j.ejca.2019.04.010
        • Muenst S
        • Soysal SD
        • Gao F
        • Obermann EC
        • Oertli D
        • Gillanders WE.
        The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer.
        Breast Cancer Res Treat. 2013; 139: 667-676https://doi.org/10.1007/s10549-013-2581-3
        • Zhou T
        • Xu D
        • Tang B
        • et al.
        Expression of programmed death ligand-1 and programmed death-1 in samples of invasive ductal carcinoma of the breast and its correlation with prognosis.
        Anticancer Drugs. 2018; 29: 904-910https://doi.org/10.1097/CAD.0000000000000683
        • Bottai G
        • Raschioni C
        • Losurdo A
        • et al.
        An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers.
        Breast Cancer Res. 2016; 18: 121https://doi.org/10.1186/s13058-016-0783-4
        • Yeong J
        • Lim JCT
        • Lee B
        • et al.
        Prognostic value of CD8 + PD-1+ immune infiltrates and PDCD1 gene expression in triple negative breast cancer.
        J Immunother Cancer. 2019; 7: 34https://doi.org/10.1186/s40425-019-0499-y
        • Sun S
        • Fei X
        • Mao Y
        • et al.
        PD-1(+) immune cell infiltration inversely correlates with survival of operable breast cancer patients.
        Cancer Immunol Immunother. 2014; 63: 395-406https://doi.org/10.1007/s00262-014-1519-x
        • Tu L
        • Guan R
        • Yang H
        • et al.
        Assessment of the expression of the immune checkpoint molecules PD-1, CTLA4, TIM-3 and LAG-3 across different cancers in relation to treatment response, tumor-infiltrating immune cells and survival.
        Int J Cancer. 2020; 147: 423-439https://doi.org/10.1002/ijc.32785
        • Wang Y
        • Dong T
        • Xuan Q
        • Zhao H
        • Qin L
        • Zhang Q.
        Lymphocyte-activation gene-3 expression and prognostic value in neoadjuvant-treated triple-negative breast cancer.
        J breast cancer. 2018; 21: 124-133https://doi.org/10.4048/jbc.2018.21.2.124
        • Du H
        • Yi Z
        • Wang L
        • Li Z
        • Niu B
        • Ren G.
        The co-expression characteristics of LAG3 and PD-1 on the T cells of patients with breast cancer reveal a new therapeutic strategy.
        Int Immunopharmacol. 2020; 78106113https://doi.org/10.1016/j.intimp.2019.106113
        • Burugu S
        • Gao D
        • Leung S
        • Chia SK
        • Nielsen TO.
        TIM-3 expression in breast cancer.
        Oncoimmunology. 2018; 7e1502128https://doi.org/10.1080/2162402X.2018.1502128
        • Byun KD
        • Hwang HJ
        • Park KJ
        • et al.
        T-Cell immunoglobulin mucin 3 expression on tumor infiltrating lymphocytes as a positive prognosticator in triple-negative breast cancer.
        J breast cancer. 2018; 21: 406-414https://doi.org/10.4048/jbc.2018.21.e61
        • Zhang H
        • Xiang R
        • Wu B
        • Li J
        • Luo G.
        T-cell immunoglobulin mucin-3 expression in invasive ductal breast carcinoma: Clinicopathological correlations and association with tumor infiltration by cytotoxic lymphocytes.
        Mol Clin Oncol. 2017; 7: 557-563https://doi.org/10.3892/mco.2017.1360
        • Pruneri G
        • Lazzeroni M
        • Bagnardi V
        • et al.
        The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast.
        Ann Oncol. 2017; 28: 321-328https://doi.org/10.1093/annonc/mdw623
        • Chen XY
        • Yeong J
        • Thike AA
        • Bay BH
        • Tan PH.
        Prognostic role of immune infiltrates in breast ductal carcinoma in situ.
        Breast Cancer Res Treat. 2019; 177: 17-27https://doi.org/10.1007/s10549-019-05272-2
        • Toss MS
        • Miligy I
        • Al-Kawaz A
        • et al.
        Prognostic significance of tumor-infiltrating lymphocytes in ductal carcinoma in situ of the breast.
        Mod Pathol. 2018; 31 (Inc.): 1226-1236https://doi.org/10.1038/s41379-018-0040-8
        • Thike AA
        • Chen X
        • Koh VCY
        • et al.
        Higher densities of tumour-infiltrating lymphocytes and CD4(+) T cells predict recurrence and progression of ductal carcinoma in situ of the breast.
        Histopathology. 2020; 76: 852-864https://doi.org/10.1111/his.14055
        • Beguinot M
        • Dauplat MM
        • Kwiatkowski F
        • et al.
        Analysis of tumour-infiltrating lymphocytes reveals two new biologically different subgroups of breast ductal carcinoma in situ.
        BMC Cancer. 2018; 18: 129https://doi.org/10.1186/s12885-018-4013-6
        • Muir R
        • Aitkenhead AC.
        The healing of intra-duct carcinoma of the mamma.
        J Pathol Bacteriol. 1934; 38: 117-127https://doi.org/10.1002/PATH.1700380202
        • Rosen PP.
        Rosen's Breast Pathology.
        Lippincott Williams & Wilkins, Mexico2001
        • Morita M
        • Yamaguchi R
        • Tanaka M
        • et al.
        CD8(+) tumor-infiltrating lymphocytes contribute to spontaneous "healing" in HER2-positive ductal carcinoma in situ.
        Cancer Med. 2016; 5: 1607-1618https://doi.org/10.1002/cam4.715
        • Ubago JM
        • Blanco LZ
        • Shen T
        • Siziopikou KP.
        The PD-1/PD-L1 Axis in HER2+ Ductal Carcinoma In Situ (DCIS) of the breast.
        Am J Clin Pathol. 2019; 152: 169-176https://doi.org/10.1093/ajcp/aqz020